The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington's disease

Sci Rep. 2017 Jun 21;7(1):4014. doi: 10.1038/s41598-017-04256-w.

Abstract

Helping neurons to compensate for proteotoxic stress and maintain function over time (neuronal compensation) has therapeutic potential in aging and neurodegenerative disease. The stress response factor FOXO3 is neuroprotective in models of Huntington's disease (HD), Parkinson's disease and motor-neuron diseases. Neuroprotective compounds acting in a FOXO-dependent manner could thus constitute bona fide drugs for promoting neuronal compensation. However, whether FOXO-dependent neuroprotection is a common feature of several compound families remains unknown. Using drug screening in C. elegans nematodes with neuronal expression of human exon-1 huntingtin (128Q), we found that 3ß-Methoxy-Pregnenolone (MAP4343), 17ß-oestradiol (17ßE2) and 12 flavonoids including isoquercitrin promote neuronal function in 128Q nematodes. MAP4343, 17ßE2 and isoquercitrin also promote stress resistance in mutant Htt striatal cells derived from knock-in HD mice. Interestingly, daf-16/FOXO is required for MAP4343, 17ßE2 and isoquercitrin to sustain neuronal function in 128Q nematodes. This similarly applies to the GSK3 inhibitor lithium chloride (LiCl) and, as previously described, to resveratrol and the AMPK activator metformin. Daf-16/FOXO and the targets engaged by these compounds define a sub-network enriched for stress-response and neuronally-active pathways. Collectively, these data highlights the dependence on a daf-16/FOXO-interaction network as a common feature of several compound families for prolonging neuronal function in HD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects
  • Aging / genetics
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans Proteins / genetics*
  • Drug Evaluation, Preclinical
  • Forkhead Box Protein O3 / genetics*
  • Forkhead Transcription Factors / genetics*
  • Gene Expression Regulation / drug effects
  • Gene Knock-In Techniques
  • Humans
  • Huntingtin Protein / genetics*
  • Huntington Disease / drug therapy*
  • Huntington Disease / genetics
  • Huntington Disease / pathology
  • Lithium Chloride / administration & dosage
  • Mice
  • Neurons / drug effects
  • Neurons / pathology
  • Pregnenolone / administration & dosage
  • Quercetin / administration & dosage
  • Quercetin / analogs & derivatives

Substances

  • Caenorhabditis elegans Proteins
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • HTT protein, human
  • Huntingtin Protein
  • daf-16 protein, C elegans
  • isoquercitrin
  • Pregnenolone
  • Quercetin
  • Lithium Chloride